Locally Synthesized Calcitonin Gene-Related Peptide Has a Critical Role in Peripheral Nerve Regeneration

Abstract Calcitonin gene-related peptide (CGRP) is a neuropeptide that has an important anti-inflammatory role in the immune system. Research has shown that CGRP is an integral part in peripheral nerve regeneration by (1) suppressing tumor necrosis factor-α, (2) forming an initial nerve bridge by increasing fibroblast motility and extracellular matrix synthesis, (3) vascularizing the spinal cord injury site, and (4) inducing Schwann cell (SC) proliferation. In this treatise, the following hypotheses will be explored: (1) CGRP is induced by c-Jun to regulate SC dedifferentiation, (2) CGRP promotes the chemotaxic migration of SCs along the nerve bridge, and (3) CGRP induces myelinophagy by activating various signaling pathways, such as p38 mitogen-activated protein kinase and Raf/extracellular signal-regulated kinase. These processes provide a framework for understanding the role of CGRP in peripheral nerve regeneration, which may be important in developing better strategies for nerve repair and gaining further insight into demyelinating diseases.

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Calcitonin Gene-Related Peptide and Peripheral Nerve Regeneration

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1992.tb22782.x ◽

1992 ◽

Vol 657 (1 Calcitonin Ge) ◽

pp. 351-360 ◽

Cited By ~ 37

Author(s):

F. L. DUMOULIN ◽

G. RAIVICH ◽

C. A. HAAS ◽

P. LAZAR ◽

M. REDDINGTON ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Peripheral Nerve Regeneration ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Calcitonin Gene

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A role for calcitonin gene-related peptide in peripheral nerve regeneration

Regulatory Peptides ◽

10.1016/0167-0115(91)90467-u ◽

1991 ◽

Vol 34 (2) ◽

pp. 126 ◽

Cited By ~ 2

Author(s):

F.L. Dumoulin ◽

C.A. Haas ◽

P. Lazar ◽

G. Raivich ◽

M. Reddington ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Peripheral Nerve Regeneration ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Calcitonin Gene

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Increased Calcitonin Gene-Related Peptide and Macrophages Are Involved in Astragalus membranaceus-Mediated Peripheral Nerve Regeneration in Rats

The American Journal of Chinese Medicine ◽

10.1142/s0192415x18500040 ◽

2018 ◽

Vol 46 (01) ◽

pp. 69-86 ◽

Cited By ~ 6

Author(s):

Chung-Chia Chen ◽

Ling-Chuan Chang ◽

Chun-Hsu Yao ◽

Yuan-Man Hsu ◽

Jia-Horng Lin ◽

...

Keyword(s):

Growth Factor ◽

Peripheral Nerve ◽

Nerve Regeneration ◽

Calcitonin Gene Related Peptide ◽

Astragalus Membranaceus ◽

High Dose ◽

Nerve Growth ◽

Expression Levels ◽

Related Peptide ◽

Calcitonin Gene

Astragalus membranaceus (AM) is one of 50 fundamental herbs in traditional Chinese medicine. Previous studies have shown that AM extract can be a potential nerve growth-promoting factor, being beneficial for the growth of peripheral nerve axons. We further investigated the effects of AM extract on regeneration in a rat sciatic nerve transection model. Rats were divided into three groups ([Formula: see text]): normal saline (intraperitoneal) as the control, and 1.5[Formula: see text]g/kg or 3.0[Formula: see text]g/kg of AM extract (every other day for four weeks), respectively. We evaluated neuronal electrophysiology, neuronal connectivity, macrophage infiltration, expression levels and location of calcitonin gene-related peptide (CGRP), and expression levels of both nerve growth factors (NGFs) and immunoregulatory factors. In the high-dose AM group, neuronal electrophysiological function (measured by nerve conductive velocity and its latency) was significantly improved ([Formula: see text]). Expression levels of CGRP and macrophage density were also drastically enhanced ([Formula: see text]). Expression levels of fibroblast growth factor (FGF), NGF, platelet-derived growth factor (PDGF), transforming growth factor-[Formula: see text], interleukin-1 (IL-1), and interferon (IFN)-[Formula: see text] were reduced in the high-dose AM group ([Formula: see text]), while FGF, NGF, PDGF, IL-1, and IFN-[Formula: see text] were increased in the low-dose AM group ([Formula: see text]). These results suggest that AM can modulate local inflammatory conditions, enhance nerve regeneration, and potentially increase recovery of a severe peripheral nerve injury.

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Perivascular Hedgehog responsive cells play a critical role in peripheral nerve regeneration via controlling angiogenesis

Neuroscience Research ◽

10.1016/j.neures.2021.06.003 ◽

2021 ◽

Author(s):

Yurie Yamada ◽

Jun Nihara ◽

Supaluk Trakanant ◽

Takehisa Kudo ◽

Kenji Seo ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Peripheral Nerve Regeneration ◽

Critical Role

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Importance of Adult Dmbx1 in Long-Lasting Orexigenic Effect of Agouti-Related Peptide

Endocrinology ◽

10.1210/en.2015-1560 ◽

2016 ◽

Vol 157 (1) ◽

pp. 245-257 ◽

Cited By ~ 1

Author(s):

Seiichiro Hirono ◽

Eun Young Lee ◽

Shunsuke Kuribayashi ◽

Takahiro Fukuda ◽

Naokatsu Saeki ◽

...

Keyword(s):

Mouse Strain ◽

Energy Homeostasis ◽

Expression Patterns ◽

Critical Role ◽

Fetal Brain ◽

Cre Recombinase ◽

Calcitonin Gene Related Peptide ◽

Adult Brain ◽

Related Peptide ◽

Calcitonin Gene

Abstract Dmbx1 is a brain-specific homeodomain transcription factor expressed primarily during embryogenesis, and its systemic disruption (Dmbx1−/−) in the ICR mouse strain resulted in leanness associated with impaired long-lasting orexigenic effect of agouti-related peptide (AgRP). Because spatial and temporal expression patterns of Dmbx1 change dramatically during embryogenesis, it remains unknown when and where Dmbx1 plays a critical role in energy homeostasis. In the present study, the physiological roles of Dmbx1 were examined by its conditional disruption (Dmbx1loxP/loxP) in the C57BL/6 mouse strain. Although Dmbx1 disruption in fetal brain resulted in neonatal lethality, its disruption by synapsin promoter-driven Cre recombinase, which eliminated Dmbx1 expression postnatally, exempted the mice (Syn-Cre;Dmbx1loxP/loxP mice) from lethality. Syn-Cre;Dmbx1loxP/loxP mice show mild leanness and impaired long-lasting orexigenic action of AgRP, demonstrating the physiological relevance of Dmbx1 in the adult. Visualization of Dmbx1-expressing neurons in adult brain using the mice harboring tamoxifen-inducible Cre recombinase in the Dmbx1 locus (Dmbx1CreERT2/+ mice) revealed Dmbx1 expression in small numbers of neurons in restricted regions, including the lateral parabrachial nucleus (LPB). Notably, c-Fos expression in LPB was increased at 48 hours after AgRP administration in Dmbx1loxP/loxP mice but not in Syn-Cre;Dmbx1loxP/loxP mice. These c-Fos-positive neurons in LPB did not coincide with neurons expressing Dmbx1 or melanocortin 4 receptor but did coincide with those expressing calcitonin gene-related peptide. Accordingly, Dmbx1 in the adult LPB is required for the long-lasting orexigenic effect of AgRP via the neural circuitry involving calcitonin gene-related peptide neurons.

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Peripheral nerve section induces increased levels of calcitonin gene-related peptide (CGRP)-like immunoreactivity in axotomized motoneurons

Experimental Brain Research ◽

10.1007/bf00228891 ◽

1990 ◽

Vol 79 (1) ◽

Cited By ~ 77

Author(s):

U. Arvidsson ◽

H. Johnson ◽

F. Piehl ◽

S. Cullheim ◽

T. H�kfelt ◽

...

Keyword(s):

Peripheral Nerve ◽

Calcitonin Gene Related Peptide ◽

Nerve Section ◽

Related Peptide ◽

Calcitonin Gene

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Rat peripheral nerve components release calcitonin gene-related peptide and prostaglandin E2 in response to noxious stimuli: evidence that nervi nervorum are nociceptors

Neuroscience ◽

10.1016/s0306-4522(98)00731-3 ◽

1999 ◽

Vol 92 (1) ◽

pp. 319-325 ◽

Cited By ~ 84

Author(s):

S.K. Sauer ◽

G.M. Bove ◽

B. Averbeck ◽

P.W. Reeh

Keyword(s):

Peripheral Nerve ◽

Prostaglandin E2 ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Calcitonin Gene ◽

Rat Peripheral Nerve ◽

Noxious Stimuli

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Involvement of calcitonin gene-related peptide and CCL2 production in CD40-mediated behavioral hypersensitivity in a model of neuropathic pain

Neuron Glia Biology ◽

10.1017/s1740925x12000026 ◽

2011 ◽

Vol 7 (2-4) ◽

pp. 117-128 ◽

Cited By ~ 9

Author(s):

Jennifer T. Malon ◽

Swathi Maddula ◽

Harmony Bell ◽

Ling Cao

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Calcitonin Gene Related Peptide ◽

Mechanical Hypersensitivity ◽

Related Peptide ◽

Calcitonin Gene ◽

Ccl2 Production

The neuropeptide calcitonin gene-related peptide (CGRP) is known to play a pro-nociceptive role after peripheral nerve injury upon its release from primary afferent neurons in preclinical models of neuropathic pain. We previously demonstrated a critical role for spinal cord microglial CD40 in the development of spinal nerve L5 transection (L5Tx)-induced mechanical hypersensitivity. Herein, we investigated whether CGRP is involved in the CD40-mediated behavioral hypersensitivity. First, L5Tx was found to significantly induce CGRP expression in wild-type (WT) mice up to 14 days post-L5Tx. This increase in CGRP expression was reduced in CD40 knockout (KO) mice at day 14 post-L5Tx. Intrathecal injection of the CGRP antagonist CGRP8–37 significantly blocked L5Tx-induced mechanical hypersensitivity. In vitro, CGRP induced glial IL-6 and CCL2 production, and CD40 stimulation added to the effects of CGRP in neonatal glia. Further, there was decreased CCL2 production in CD40 KO mice compared to WT mice 21 days post-L5Tx. However, CGRP8–37 did not significantly affect spinal cord CCL2 production following L5Tx in WT mice. Altogether, these data suggest that CD40 contributes to the maintenance of behavioral hypersensitivity following peripheral nerve injury in part through two distinct pathways, the enhancement of CGRP expression and spinal cord CCL2 production.

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